Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have emerged as attractive treatment options for various cancers. One of their applications is in the treatment of microsatellite instability high (MSI-H) tumors, in which microsatellite sequences accumulate mutations due to defective mismatch repair (dMMR). MSI-H tumors carry a high mutation burden, typically express cancer-specific neoantigens, and are sensitive to PD-1/PD-L1 blockade [1, 2]. The prevalence of dMMR/MSI-H varies according to cancer type. Cancers with the highest rates of MSI-H (> 10%) include colorectal cancer (CRC) and gastric cancer (GC) [2, 3].

In previously treated advanced dMMR/MSI-H cancers, improved treatments have been needed because of limited treatment options and poor prognosis [4‐9]. PD-1/PD-L1-targeting monoclonal antibodies represent a significant advance in the treatment of these tumors. Two PD-1-targeting monoclonal antibodies, pembrolizumab and nivolumab, have been approved in the USA for the treatment of metastatic dMMR/MSI-H CRC in patients who have failed standard chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan [10, 11]. Pembrolizumab has also been approved as a first-line treatment for patients with advanced dMMR/MSI-H CRC and in patients with other dMMR/MSI-H solid tumor types who have failed at least one prior systemic treatment, and was the first drug granted a tumor-agonistic indication by the US Food & Drug Administration. In multicenter phase 2 clinical trials in patients with advanced dMMR/MSI-H cancers, pembrolizumab [12‐14] and nivolumab [11, 15] have shown acceptable toxicity and promising efficacy, with objective response rates (ORRs) of 28–36%. However, pembrolizumab, nivolumab, and all other approved PD-1/PD-L1-targeting monoclonal antibodies are administered by intravenous infusion, which can be inconvenient for patients and increase utilization of medical resources, and in a minority of patients can cause life-threatening infusion reactions [10, 11].

Single-domain antibodies lacking the immunoglobulin light chain are a possible alternative to full monoclonal antibodies. Although they tend to have a short half-life due to rapid renal clearance, they are more soluble and stable than full monoclonal antibodies and, importantly, more rapidly penetrate tissues; collectively, these properties enable subcutaneous administration [16]. The first single-domain antibody received US Food & Drug Administration approval in 2019 [17, 18], but single-domain antibodies have not yet been approved for the treatment of cancer.

Envafolimab is a humanized camel-derived single-domain anti-PD-L1 antibody fused to a human immunoglobulin F_c fragment to prolong its half-life [19]. It has the potential to be a major advance in the treatment of cancer because it would be the first subcutaneous PD-1/PD-L1-targeting single-domain antibody for treating cancer. The full therapeutic dose of envafolimab (150 mg) can be delivered as a single 0.75-ml subcutaneous injection in under 30 s due to the high solubility of the fusion protein (200 mg/mL). Across phase 1 dose-escalation studies in advanced cancers, confirmed response rates ranged from 14 to 18%, and no infusion reactions and only two grade 3 treatment-related adverse events (AEs) were reported [20‐22]. Pharmacokinetic analyses of envafolimab monotherapy showed that 150 mg once weekly would provide a sufficient exposure in cancer patients [23]. Here, we describe the results of a pivotal phase 2 study of the efficacy and safety of envafolimab in adults with advanced dMMR/MSI-H solid tumors.

The current study was the first pivotal phase 2 trial to examine the efficacy and safety of a single-domain antibody in the treatment of cancer [18]. This study showed that envafolimab, a single-domain anti-PD-L1 antibody fusion protein administered by subcutaneous injection, was effective and had acceptable safety for the treatment of previously treated advanced dMMR/MSI-H solid tumors. Efficacy of envafolimab was similar to that reported in phase 2 trials for the intravenously administered monoclonal antibodies pembrolizumab and nivolumab in previously treated metastatic dMMR/MSI-H CRC [13, 15] and for pembrolizumab in previously treated dMMR/MSI-H non-CRC [14]. In addition to demonstrating the safety and efficacy of a subcutaneously administered single-domain antibody for treating cancer, the current study is the first to provide evidence that a single-domain anti-PD-L1 antibody has similar efficacy as full anti-PD-1 monoclonal antibodies in treating dMMR/MSI-H cancer.

Overall rates of grade 3 and 4 irAEs and drug-related AEs were in line with expectations for a monoclonal antibody targeting PD-L1 signaling [13, 15]. The most commonly reported drug-related TEAEs included decreased white blood cell count, asthenia, rash, hypothyroidism, and decreased neutrophil count, which have been reported for other PD-1/PD-L1 inhibitors [13, 15, 25, 26]. There were no infusion reactions, and injection site reactions were infrequent and of mild or moderate severity. Importantly, no cases of immune-related pneumonitis or colitis were reported in this study as of the data cutoff.

Since their initial approval in 2014, PD-1/PD-L1-targeting monoclonal antibodies have rapidly become a pillar of cancer treatment across many tumor types. However, because they are administered by intravenous infusion, infusion reactions can occur. Subcutaneous injection of envafolimab avoids the infusion reactions, though infrequent, seen with pembrolizumab and nivolumab [10, 11]. Also, envafolimab takes less than 30 s to administer, compared with 30 min or longer for intravenous infusion of currently available PD-1/PD-L1-targeting monoclonal antibodies. These represent significant advantages for patients and medical staff. They are expected to improve patient compliance and reduce medical resource utilization and are pertinent during the ongoing pandemic.

These advantages of envafolimab are expected to grow, because PD-1/PD-L1-targeting monoclonal antibodies are moving into first-line and adjuvant/neoadjuvant treatment across tumor types where chronic dosing is common. It is therefore noteworthy that, for patients with CRC in the present study, efficacy outcomes (including ORR and PFS) tended to be better for those who had failed one prior line of therapy than for those who had failed at least two prior lines of therapy. This suggests that envafolimab may be more effective in earlier-line treatment of advanced dMMR/MSI-H CRC, as reported for pembrolizumab [13, 27]. However, these observations should be interpreted with caution due to the limited numbers of patients.

The ORR and DoR were generally similar across tumor types, despite the different test methods applied (local versus central), an observation also made for pembrolizumab [28] and nivolumab [29]. Time to response and temporal response patterns for envafolimab were also consistent with pembrolizumab and nivolumab in dMMR/MSI-H solid tumors [13‐15]. The results of this study support dMMR/MSI-H status as a valid tumor-agnostic biomarker for PD-L1 inhibitors. However, limitations of the study include the single-arm design, small sample for tumor types other than CRC and GC, and potential negative impact on efficacy due to possible heterogeneity of MSI-H status not detected by available tests.

As the first single-domain PD-L1-targeting antibody administered by rapid subcutaneous injection, envafolimab has the potential to be a significant advance in the treatment of cancer. To confirm the current findings and generate more data for underrepresented tumor types in a larger population, the study is being expanded to become a confirmatory trial enrolling at least 200 patients with advanced dMMR/MSI-H solid tumors. Envafolimab is also being developed in other cancer indications where PD-1/PD-L1-targeting monoclonal antibodies have been shown to be effective.